Docetaxel belongs to taxane drugs. The main mechanism of action thereof involves interfering with mitosis, promoting the assembly of microtubules and prohibiting the disassembly of microtubules, so as to inhibit the differentiation of tumor cells, and finally lead to death thereof. Currently, docetaxel is approved for the treatment of various indications such as breast cancer, non-small cell lung cancer, prostate cancer and the like in major countries worldwide, and it constitutes the most commonly used or standard therapy for the treatment of these cancers. Furthermore, in subsequent clinical studies, docetaxel is also widely investigated for the treatment of gastric cancer, head and neck tumor, esophageal cancer, ovarian cancer, and the like. Treatment of these indications with docetaxel is expected to be approved in Europe and America later.
Docetaxel has poor water solubility. Presently, the formulation of docetaxel commercially available is a liquid dosage form for infusion in a concentrated form, and the dosage regimen normally recommended is intravenous infusion of 75 mg/m2 within 1 hour, once every 3 weeks. A docetaxel injection comprises a drug concentrate, which is formed by dissolving docetaxel in a solvent, Tween-80, accompanied with a diluent containing 13% ethanol. However, pre-application of an anti-allergic drug is necessary during clinical administration due to the hemolytic property of Tween-80, which tends to cause allergic reactions including dyspnea, hypotension, angioedema, rubella, shock, etc. when it is intravenously injected. Moreover, the high viscosity of Tween-80 also brings about great inconvenience in clinical application.
In order to overcome defects of the docetaxel injection, such as toxic side effects and the like, CN103830181A discloses a lyophilized liposome comprising an inclusion complex of docetaxel with cyclodextrin, wherein the stability of docetaxel is improved by inclusion with cyclodextrin, and an improved targeting property and reduced toxic side effects are achieved with the liposome particle system. However, the toxicity of cyclodextrin per se limits the application thereof. CN101773465A discloses a polymeric micellar system stabilized by amino acids, and a polymeric micelle comprising docetaxel is developed. It is shown that the physical appearance of the polymeric micelle with amino acids can be stable for more than 5 days, while the polymeric micelle without amino acids can be stable only for 30 minutes. However, the degradation of high molecular polymers (e.g., mPEG-PLA, etc.) employed in polymeric micelles after being injected into a body is quite slow, and may even last for more than 1 year. In view of such potential safety issues, no polymeric micelle product of docetaxel has been approved for marketing by the FDA in the United States. As such, although improved targeting properties and reduced toxic side effects are achieved with these particle systems, the application thereof is limited by their defects.
CN103054798A discloses a docetaxel albumin nanoparticle (ABI-008), wherein citric acid (or a salt thereof) is added to a composition of docetaxel and albumin, such that the physical stability of a solution of the docetaxel albumin nanoparticle is increased, and no precipitation or sedimentation phenomenon is observed for at least 8 hours after reconstitution or rehydration.
However, for improving the stability of docetaxel, in addition to control the physical stability of particles in a solution, it is more important to reduce the chemical degradation of docetaxel. At present, studies focusing on reducing the chemical degradation of docetaxel are quite limited in the prior art, and no method for improving such degradation is available yet.
Docetaxel per se can undergo a variety of degradation pathways under various conditions, and degradation products resulted therefrom render corresponding changes in the activity and/or toxicity of docetaxel, and may even significantly affect the activity and/or toxicity thereof. The main factors affecting the degradation of docetaxel include temperature, acidic and basic solvents, oxidants, reductants and light, etc.
In a basic, neutral or strong acidic medium, one of the main degradation pathways of docetaxel is the epimerization of 7-hydroxy, which results in 7-epi-docetaxel through retro-aldol reaction.
Bornique et al. (Drug Metabolism and Disposition, Vol. 30, No. 11, pp. 1149-1152, 2002) investigates the interaction between docetaxel and 7-epi-docetaxel with recombinant human cytochrome P4501B1 (hCYP1B1). hCYP1B1 is a common cytochrome in human tumor cells, and is mainly related to drug resistance of chemotherapy drugs (including docetaxel). The in vitro test shows that the activity of hCYP1B1 can be increased by more than 7 times by 7-epi-docetaxel, thus it is confirmed that the degradation product of docetaxel, 7-epi-docetaxel, reduces the activity of docetaxel.
CN101415416A discloses inhibition of the production of 7-epi-docetaxel in a pharmaceutical composition of docetaxel and polysorbate 80 by adding an organic acid with a pKa value of 2.5 to 4.5 as a docetaxel degradation inhibitor.
However, the inventors of the present invention have demonstrated through experimentation that addition of an agent such as tartaric acid, citric acid, ascorbic acid or another organic acid with a pKa value of 2.5 to 4.5 etc. into a composition of docetaxel and albumin cannot effectively inhibit the production of 7-epi-docetaxel, which, instead, may even increase. This indicates that the above agents decrease the chemical stability of the composition, and affect the safety of the final formulation.
CN103054798A discloses addition of a stabilizer such as citric acid (or a salt thereof) and the like into a composition of docetaxel and albumin. Although the stabilizer enhances the physical stability of the solution of the docetaxel albumin nanoparticle, the inhibitory effect thereof on the production of 7-epi-docetaxel is not mentioned.
It has been demonstrated through experimentation that conventional stabilizers such as citric acid (or a salt thereof) and the like cannot always effectively inhibit the production of 7-epi-docetaxel, and sometimes the production thereof may be accelerated. During storage, the amount of 7-epi-docetaxel produced far exceeds 2.0%, which would results in potential safety issues in clinical medication.
One of the challenges in search for a method for inhibiting the production of 7-epi-docetaxel is that, during the storage of a docetaxel albumin nanoparticle, the presence of a large amount of hydrogen bonds in the polypeptidic structure of albumin is unfavorable for the stability of docetaxel and accelerates the retro-aldol reaction, which result in the epimerization of 7-hydroxyl, rendering the formation and steady increase of the 7-epi-docetaxel impurity.
As such, it is an urgent problem to be solved in the art to find a method for inhibiting the production of 7-epi-docetaxel in a pharmaceutical composition of docetaxel.